Abstract
Keywords
To the Editor,
Tuberculosis (TB) remains one of the world’s deadliest infectious diseases. According to the World Health Organization (WHO) Global Tuberculosis Report 2024, an estimated 10.8 million new TB cases and 1.25 million deaths occurred globally in 2023. For the first time since the COVID-19 pandemic, TB has regained its position as the leading infectious disease killer worldwide. Despite decades of control efforts, progress toward the WHO End TB Strategy targets have been disappointing, with only an 8.3% decline in TB incidence achieved by 2023. 1
The challenge is further compounded by drug-resistant tuberculosis (DR-TB). India bears the highest global burden, with approximately 110,000 new DR-TB cases annually. In 2022,multidrug-resistant TB (MDR-TB) detections increased by 32% compared with 2021. Conventional second-line regimens, often lasting 18–24 months and involving injectable drugs, high pill burden, and substantial toxicity, have resulted in poor adherence and unfavorable outcomes, highlighting the urgent need for shorter, safer, and more effective treatments.
A major breakthrough came with the introduction of the BPaL (bedaquiline, pretomanid, and linezolid) and BPaLM (bedaquiline, pretomanid, linezolid, and moxifloxacin) regimens. The Nix-TB trial demonstrated approximately 90% favorable outcomes with a 26-week all-oral BPaL regimen in patients with extensively drug-resistant (XDR) TB and treatment-intolerant MDR-TB. However, linezolid at 1,200 mg daily was associated with significant adverse effects, including peripheral neuropathy and myelosuppression. 2
The ZeNix trial addressed these concerns by evaluating different linezolid doses and durations. Favorable outcomes ranged from 84–93%, with the 600 mg for 26 weeks regimen offering the best balance between efficacy and safety. Subsequently, the TB-PRACTECAL trial showed that the 24-week BPaLM regimen resulted in unfavorable outcomes in only 11% of patients compared with 48% in the standard-care group, with fewer serious adverse events, leading to early trial termination due to overwhelming efficacy. 2
These findings prompted WHO in 2022 to recommend the 6-month BPaLM regimen as the preferred treatment for eligible MDR/RR-TB patients. More recently, the 2025 ATS/CDC/ERS/IDSA guidelines strongly recommended BPaL for fluoroquinolone-resistant RR-TB and BPaLM for fluoroquinolone-susceptible RR-TB in patients aged ≥14 years. Global uptake has been rapid, increasing from 1,744 patients in 2022 to approximately 34,000 in 2024.
India’s response has been commendable. In 2024, the Government of India approved and rolled out BPaLM under the National TB Elimination Programme. Given that India contributes nearly 25% of global TB cases and has the highest DR-TB burden, adoption of a shorter all-oral regimen has the potential to improve outcomes while reducing pressure on healthcare systems. 1
Nevertheless, challenges remain. Linezolid-associated toxicity, emerging bedaquiline resistance, and the need for robust drug-susceptibility testing, laboratory infrastructure, supply chains, and trained healthcare personnel continue to pose obstacles. Additionally, current global TB research funding remains far below the estimated requirement. 1
Looking ahead, the TB pipeline is encouraging, with 15 vaccine candidates and 29 drugs in clinical development, including the promising M72/AS01E vaccine. Further refinements of BPaL-based regimens, such as replacing linezolid with inhaled spectinamide 1599, may improve safety while maintaining efficacy. 3
In conclusion, BPaL and BPaLM represent a transformative advance in DR-TB treatment. Their success offers renewed hope, but their ultimate impact will depend on effective implementation, surveillance, and sustained investment in TB control and research.
